Tandem Palladium/Copper-Catalyzed Decarboxylative Approach to Benzoimidazo- and Imidazophenanthridine Skeletons

A protocol for a tandem Pd/Cu-catalyzed intermolecular cross-coupling cascade between o-bromobenzoic acids and 2-(2-bromoaryl)-1H-benzo[d]imidazoles or the corresponding imidazoles is presented. The protocol provides conceptually novel and controlled access to synthetically useful N-fused (benzo)imidazophenanthridine scaffolds with high efficiency, a broad substrate scope, and excellent functional group compatibility.

B enzoimidazo-and imidazophenanthridines represent an important class of N-heterocycles that display highly attractive biological, photophysical, and aggregation properties (Figure 1, top). Several (dihydro)imidazophenanthridine derivatives were identified as potent DNA-binding agents with anticancer activities. 1 A naturally occurring alkaloid featuring an imidazophenanthridine core, namely, zephycandidine A, displayed considerable antitumor and antiacetylcholinesterase activities, 2 prompting the synthesis and biological studies of a range of related compounds. 3 Furthermore, several (benzo)imidazophenanthridines with extended π-systems have been applied as components of organic light-emitting diodes (OLEDs), 4 while (dihydro)imidazophenanthridinium salts of polyoxometalates (POMs) were found to undergo highly unusual spontaneous self-assembly into microtubular structures. 5 To date, a number of synthetic methodologies to access such heterocyclic manifolds have been disclosed (Figure 1, middle). Palladium-catalyzed cross-coupling reactions are predominant among these methods and allow the assembly of the (benzo)imidazophenanthridine core through various bond-disconnection strategies. 6 Additionally, several photo-7 and electrochemical methods 8 have been utilized to access the same type of heterocycles. Despite these developments, affording (benzo)imidazophenanthridine derivatives in a controlled and regioselective manner remains a notable synthetic challenge. Considering our long-standing interest in the development of metalcatalyzed annulation reactions, 9 we sought to provide a straightforward and modular synthetic approach to substituted (benzo)imidazophenanthridines from simple starting materials and under mild reaction conditions. Initially, readily prepared 2-(2-bromophenyl)-1H-benzo [d]imidazole (1a) and o-bromobenzoic acid (2a) were selected as model substrates for the optimization of the reaction conditions (Scheme 1, top). Several reaction parameters were surveyed, including the palladium precursor, the auxiliary catalyst, the base, the ligand, the temperature, and the solvent. A range of palladium precursors, such as Pd(OAc) 2 , PdCl 2 and (η 3 -C 3 H 5 ) 2 Pd 2 Cl 2 , and auxiliary copper catalysts, such as CuI, CuBr, Cu(OAc) 2 , and Cu(OTf) 2 , were evaluated in DMF at 80°C (Table S3, entries 1−7, respectively). As a result, a combination of Pd(OAc) 2 and a CuI cocatalyst displayed the best reactivity, affording the benzoimidazophenanthridine product 3a in 35% yield (Scheme 1, entry 1), while copper(II) precursors were found less effective. The addition of commonly employed ligands, such as Ph 3 P, 1,10-phenanthroline (o-phen) and L-proline, had a significant influence on the reaction. Specifically, the addition of Ph 3 P increased the yield of the desired product 3a to 51% (Scheme 1, entry 2), while o-phen and L-proline proved less effective (Table S3, entries 9 and 10, respectively). Screening of inorganic bases (Table S3, entries 8, 11, and 12) revealed Cs 2 CO 3 as the optimal base. Subsequently, a survey of solvents (Table S3, entries 13−15, respectively), including DMSO, DMAc, and toluene, demonstrated their negative effect on the reaction, providing 3a in diminished yields (12−41%). Conducting the reaction at different temperatures had a dramatic effect on the reaction outcome (Table S3, entries 8 and 16−19). Therefore, the conditions from entry 3 (Scheme 1, entry 17 from Table S3) were selected as optimal for further investigation of the disclosed transformation. Control experiments in the absence of either Pd(OAc) 2 or CuI catalysts were conducted (Scheme 1, entries 4 and 5), demonstrating that both the catalysts were required for the efficient formation of product 3a. A potential role of the Cu I catalyst as a reductant for transforming the Pd II precursor into an active Pd 0 form was deemed unlikely, as the reaction with the Pd(PPh 3 ) 4 catalyst in the absence of the Cu catalyst furnished the desired product 3a in a mere 19% yield (Scheme 1, entry 6). Addition of CuI to the latter reaction replenished the tandem catalytic activity, delivering product 3a in 69% yield (Scheme 1, entry 7).
Subsequently, a range of substituted ortho-bromobenzoic acids 2 was investigated under the optimal reaction conditions (Scheme 1). Gratifyingly, 4-and 5-substituted ortho-bromobenzoic acids 2 bearing electron-withdrawing (F and Cl) or electron-donating substituents (Me and MeO) smoothly reacted with substituted benzimidazole-, imidazole-, and 1Hphenanthro[9,10-d]imidazole-based substrates 1, furnishing the desired products 4a−4h in generally high yields (64−82%). Furthermore, 4,5-disubstituted ortho-bromobenzoic acids, as well as 1-bromo-2-naphthoic acid, were compatible with the disclosed protocol, affording the expected products 4u−4z in up to 75% yields. At the same time, 1-bromo-2-naphthoic acids with electron-withdrawing substituents failed to produce the desired product. Similarly, both 3-and 6-methyl-substituted obromobenzoic acids proved inefficient and produced inseparable mixtures of products. The structures of products 3aa and 4h were unequivocally confirmed by single-crystal X-ray analysis (CCDC 2176172 and CCDC 2195117, respectively; see the Supporting Information for details). Notably, the substitution pattern in products 4a−4t and 4w−4x firmly confirms that in the disclosed transformation the C−N and C−C bonds are formed through decarboxylative and dehalogenative crosscoupling reactions, respectively.
Besides the control experiments presented in Table S3, entries 20−23, a series of additional control reactions were conducted to gain insight into the operational mechanism(s) of the disclosed transformation. Subjecting ortho-bromobenzoic acid 2a to the optimized reaction conditions in the absence of 1 afforded triphenylene 5a in 81% yield (Scheme 2, top left). The formation of such a trimerization product could indicate the involvement of benzyne as the key intermediate in both the trimerization and intermolecular cross-coupling reactions, as has been proposed for several transformations featuring similar starting materials under related conditions. 10 However, conducting the reaction with 4-or 5-substituted orthobromobenzoic acids delivered trisubstituted triphenylene derivatives 5b and 5c, respectively, displaying formal C 3h symmetry, while the metal-catalyzed [2 + 2 + 2] cycloaddition of substituted benzynes typically would produce triphenylenes as a mixture of products with C 3h and C s symmetries, favoring the latter. 10,11 This observation indirectly indicates that the disclosed trimerization proceeds through three consecutive decarboxylative cross-coupling steps rather than a [2 + 2 + 2] cycloaddition. Furthermore, conducting the trimerization reaction in the absence of the Pd or Cu catalyst either prohibited the reaction (in the absence of Pd) or greatly suppressed the formation of product 5a (17% yield in the absence of Cu), suggesting that the reaction firmly relies on tandem Pd/Cu catalysis. Next, we investigated if the C−C and C−N bonds in product 3a could be formed independently during the tandem Pd/Cu-catalyzed reaction using benzoic acid (unsubstituted and ortho-chloro or bromo-substituted) and bromobenzene as the coupling partners together with bromo-substituted benzimidazole 1a (Scheme 2, top right). As a result, no reaction was observed between 1a and either the benzoic acids or and minor mechanistic pathways for the disclosed crosscoupling between ortho-bromobenzoic acids (2) and bromosubstituted (benzo)imidazoles (1) (Scheme 2, bottom). In the major mechanistic pathway, the Cu I catalyst and orthobromobenzoic acid 2 form a carboxylate salt A, which eliminates CO 2 to afford the organocuprate species B. In parallel, the Pd 0 catalyst (formed in situ) undergoes oxidative addition to bromosubstituted (benzo)imidazole 1 to furnish the Pd II metallacycle C. In the key step of the reaction, transmetalation between species B and C concludes the copper-mediated catalytic cycle and produces the highly electron-rich Pd II species D. This species is then responsible for the formation of the C−N bond of the final product through reductive elimination, concomitantly producing Pd 0 species E. The latter undergoes facile intramolecular oxidative addition with the C−Br bond to form the Pd II species F. Finally, C−C bond formation takes place through reductive elimination in intermediate F, concluding the Pd 0 /Pd II catalytic cycle, and furnishes the desired product 3. An alternative minor mechanistic pathway enables the disclosed transformation without the involvement of Cu catalysis and becomes the major pathway under the conditions from  13 The key regioselectivity-determining step in the major pathway, that is, reductive elimination in intermediate D, represents a highly unusual example of the preferential formation of a C−N rather than C−C bond in Pd species featuring two phenyl ligands and one amide ligand. 14 Here, the observed selectivity can be potentially attributed to the oxidation state of the palladium center, Pd II , as the opposite selectivity was observed for reductive elimination from Pd IV species.
In conclusion, we have developed a novel Pd-catalyzed cascade annulation reaction of bromo-substituted benzimidazoles and o-bromobenzoic acids, providing a convenient and modular approach to a range of functionalized (benzo)imidazophenanthridines. A mechanism based on a tandem Pd/Cu decarboxylative cross-coupling pathway is proposed. Considering the practicality of this method and the importance of (benzo)imidazophenanthridine scaffolds in materials science and medicinal chemistry, the methodology described here will undoubtedly find wide applications in future synthetic endeavors.

■ ASSOCIATED CONTENT Data Availability Statement
The data underlying this study are available in the published article and its online Supporting Information.